Lartigau E, Stern S, Guichard M
Département de radiothérapie, Centre Oscar-Lambret, Lille, France.
Cancer Radiother. 2000 May-Jun;4(3):217-22. doi: 10.1016/s1278-3218(00)89097-6.
Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive drugs could be significantly increased by combination with ionising radiation or chemotherapy. Various parameters such as oxygen tension and timing of administration of the drugs could play a crucial role in the efficacy of combined treatment modalities. The aim of this study was to define the oxygen dependency of cell survival after in vitro irradiation and incubation with tirapazamine, a bioreductive drug, and cisplatin given alone or simultaneously. Two human cell lines were studied: one cell line sensitive to tirapazamine, Na11+, a pigmented melanoma with a high percentage of hypoxic cells, and a less sensitive cell line to tirapazamine, HRT18, a rectal adenocarcinoma. Gas changes were made to study cell survival at four different oxygen concentrations (pO2): air (20.9% O2), 10.2 and 0.2% O2. Cells were incubated with tirapazamine and cisplatin alone or combined for one hour at 37 degrees C, then irradiated and cultured. For Na11+, cell survival after irradiation was comparable in air and at 10% oxygen with the two drugs given alone or combined. At 2 and 0.2% oxygen, cell killing was largely increased by tirapazamine and was not modified by the addition of cisplatin. For HRT18, cell survival was not modified when cisplatin was added to radiation, whatever the oxygen partial pressure. At low pO2 (2 and 0.2%) the cytotoxic effect of tirapazamine was not significantly decreased by the addition of cisplatin. When cytotoxic and bioreductive drugs are combined to radiation, the magnitude of the observed effect is highly dependent on the partial oxygen pressure and on the sensitivity of the cell line to the individual drugs. This has very important implications for clinical strategies based on combined chemo-radiotherapy.
近期数据表明，与电离辐射或化疗联合使用时，生物还原药物的体外和体内细胞毒性可显著增强。诸如氧张力和药物给药时间等各种参数可能在联合治疗方式的疗效中发挥关键作用。本研究的目的是确定在体外照射以及与生物还原药物替拉扎明和单独或同时给予的顺铂孵育后细胞存活的氧依赖性。研究了两种人类细胞系：一种对替拉扎明敏感的细胞系Na11 +，一种具有高比例缺氧细胞的色素沉着黑色素瘤，以及一种对替拉扎明不太敏感的细胞系HRT18，一种直肠腺癌。通过改变气体来研究在四种不同氧浓度（pO2）下的细胞存活情况：空气（20.9% O2）、10.2% O2和0.2% O2。细胞在37℃下单独或联合用替拉扎明和顺铂孵育1小时，然后进行照射和培养。对于Na11 +，单独或联合给予两种药物时，照射后在空气和10%氧气条件下的细胞存活情况相当。在2%和0.2%氧气条件下，替拉扎明大大增加了细胞杀伤作用，而添加顺铂并未改变这种情况。对于HRT18，无论氧分压如何，将顺铂添加到放疗中时细胞存活情况均未改变。在低pO2（2%和0.2%）时，添加顺铂并未显著降低替拉扎明的细胞毒性作用。当细胞毒性和生物还原药物与放疗联合使用时，观察到的效应大小高度依赖于氧分压以及细胞系对各个药物的敏感性。这对于基于联合放化疗的临床策略具有非常重要的意义。
